Nomogram for soiling prediction in postsurgery hirschsprung children: a retrospective study

Purpose: The aim of this study was to develop a nomogram for predicting the probability of postoperative soiling in patients aged greater than 1 year operated for Hirschsprung disease (HSCR). Materials and methods: The authors retrospectively analyzed HSCR patients with surgical therapy over 1 year of age from January 2000 and December 2019 at our department. Eligible patients were randomly categorized into the training and validation set at a ratio of 7:3. By integrating the least absolute shrinkage and selection operator [LASSO] and multivariable logistic regression analysis, crucial variables were determined for establishment of the nomogram. And, the performance of nomogram was evaluated by C-index, area under the receiver operating characteristic curve, calibration curves, and decision curve analysis. Meanwhile, a validation set was used to further assess the model. Results: This study enrolled 601 cases, and 97 patients suffered from soiling. Three risk factors, including surgical history, length of removed bowel, and surgical procedures were identified as predictive factors for soiling occurrence. The C-index was 0.871 (95% CI: 0.821–0.921) in the training set and 0.878 (95% CI: 0.811–0.945) in the validation set, respectively. And, the AUC was found to be 0.896 (95% CI: 0.855−0.929) in the training set and 0.866 (95% CI: 0.767−0.920) in the validation set. Additionally, the calibration curves displayed a favorable agreement between the nomogram model and actual observations. The decision curve analysis revealed that employing the nomogram to predict the risk of soiling occurrence would be advantageous if the threshold was between 1 and 73% in the training set and 3–69% in the validation set. Conclusion: This study represents the first efforts to develop and validate a model capable of predicting the postoperative risk of soiling in patients aged greater than 1 year operated for HSCR. This model may assist clinicians in determining the individual risk of soiling subsequent to HSCR surgery, aiding in personalized patient care and management.


Introduction
Hirschsprung disease (HSCR), which affects ~1 per 5000 children, is a common congenital deformity that caused by the incomplete craniocaudal migration of enteric neural crest cells during embryological development [1,2] .Presently, the optimal treatment for HSCR is surgery to remove the aganglionic bowel [3] .With the significant progress have been achieved in the management of HSCR, the quality of life of patients has been greatly improved.However, certain individuals still experienced various postoperative complications, especially the soiling, remains affecting the quality of life of HSCR patients [4,5] .
Soiling, characterized by the involuntary leakage of stool that requires a change of underwear or diapers, is a prevalent complication following the surgery of HSCR [6,7] .The currently available reports on the prevalence of soiling following the surgery for HSCR vary widely [6] .A new systematic review indicated that the prevalence of soiling range from 4.1 to 54.5% after transanal endorectal pull-through (TEPT) and from 0 to 37.5% after laparoscopic-assisted TEPT (LAPT) [8] .In theory, the incidence of postoperative soiling should be low for HSCR patients undergoing surgical procedures, as patients are born with a fully developed anal anatomy, including intact sensation and functional voluntary sphincters.Additionally, a well-experienced surgeon and the availability of surgical techniques were responsible for the function of the anal canal, thus to maintain regular intestinal function postoperatively [9] .At present, the precise mechanism underlying

HIGHLIGHTS
• This is the first study to establish and validate a model for predicting the risk of soiling in patients aged greater than 1 years operated for Hirschsprung disease.• In this work, we determined that surgical history, length of removed bowel, and surgical procedures were the main factors associated with soling in patients with Hirschsprung disease.• The developed predictive model will be valuable in identification and stratification of patients following operative management.
soiling in patients with HSCR remains incompletely understood, although it may be related to several factors, such as abnormal anal canal sensation, inadequate sphincter control, and the degree of bowel dysmotility [10] .
In the context of soiling in patients with HSCR, previous studies mainly focus on individuals who underwent surgery before the age of 1 year [6,11] .Nevertheless, it is a well-established fact that infants under the age of one year possess inadequate bowel control capabilities [12] , making it difficult to assess the condition of soiling.Simultaneously, soiling can result from various factors, including external causes like medications as well as unknown elements related to certain conditions such as Down syndrome [13,14] .Importantly, infants are especially susceptible to these various soiling factors.Therefore, we first determined factors associated with soiling occurrence in patients over the age of one who underwent surgery for HSCR.
This study is the first to establish and validate a model for predicting the risk of soiling in patients with HSCR following surgical therapy beyond the age of 1 year.We proposed that this nomogram be readily accessible to clinicians, enabling them to easily estimate the risk of soiling in their patients.

Patients
This retrospective study was conducted on patients diagnosed with HSCR who underwent surgical treatment at our hospital department from January 2000 to December 2019.This research study was reviewed and approved by the Ethics Committee at Hospital, waiving the requirement for informed consent in alignment with the Declaration of Helsinki.The diagnosis of HSCR was established through preoperative examinations, which included barium enema, anorectal manometry, and suction rectal biopsy.Additionally, postoperative pathological examination was conducted to further confirm the diagnosis.All operations were performed in accordance with the standard procedures by experienced surgical groups in our department.

Study protocol
The work was approved by the Ethics Committee and registered on Clinicaltrial.gov.It was conducted and reported in line with the strengthening the reporting of cohort, cross-sectional and case-control studies in surgery (STROCSS) criteria [15] .

Definition of soiling
This study refers to the diagnostic criteria for soiling as described in the published literature [16,17] .Based on the previously established criteria and clinical experience, patients who experienced soiling persisting for more than 6 months following surgery were ultimately identified for inclusion in this study.In this study, patients with Down's syndrome, and other established syndromes potentially contributed to maldevelopment were excluded as previous described [18] .In addition, patients who had their initial surgery at another institution were excluded from the study, as well as any participants received staged treatment or had missing data related to soiling.A study flow chart is illustrated in Figure 1.

Data collection and potential predictors
In this study, we collected the clinical information about patients from a thorough review of relevant literatures and clinical judgement.These data included the age for definitive surgery, sex, weight at operation, premature delivery history, family history, meconium, duration of constipation, conservative treatment, surgical history, surgical techniques, length of removed bowel, surgical procedure, and soiling status.The surgical techniques included LAPT, laparotomy-assisted endorectal pull-through (LEPT), and TEPT.Length of removed bowel included left colectomy, subtotal ectomy, and total colectomy.Surgical procedures were categorized as Soave, Heart-Shaped, Rebbein, Duhamel, and others.Data with a deletion rate of greater than or equal to 20% were excluded from the analysis.The trimming method was introduced to address with abnormal values and a multiple imputation method was employed to interpolate missing data [19,20] .

Logistic regression analysis and nomogram model development
A total of 601 patients were randomly assigned into training and validation set in a 7:3 ratio as previous reported [21,22] .No significant differences were observed in demographic and clinical characteristics between the training and validation sets.To determine potential predictive factors, the training set was subjected to LASSO regression analysis, which effectively eliminated several irrelevant or multicollinearity independent variables to reduce high-dimensional data [23] .Then, the multivariable logistic regression analysis was applied to determine the variables of soiling in patients with HSCR following surgery over one year of age.Finally, a nomogram was created based on the training set and validated in the validation set.

Apparent performance of the nomogram
Discrimination and calibration were employed to assess and test the predictive accuracy of the established model [24] .Harrell's concordance index (C-index) and the receiver operating characteristic (ROC) curve (AUC) were generated to estimate the discrimination of the nomogram [25] .A C-index close to 1 indicates a high level of predictive ability of the model.Additionally, an AUC greater than 0.80 indicates relatively good discrimination [26,27] .The calibration of the nomogram was accompanied with the Hosmer-Lemeshow test were developed to determine the consistency between the predicted and observed occurrence of soiling [28] .Lastly, DCA was performed to evaluate clinical practicability of the nomograms [29] .Both discrimination and calibration were assessed by bootstrapping with 1000 resamples.

Statistical analysis
For parameters with continuous variables, the normal distribution was expressed as mean SD, and the skewed distribution was presented as median [M] and quartile range [Q25 − Q75].Continuous data between two groups were compared using the independent t-test.The unequal variance t-test was used to compare data between groups with unequal variances.In cases of skewed distribution, the Mann-Whitney U test was employed.Furthermore, categorical data were compared using χ 2 or Fisher's exact test.Statistical analysis was performed using R Software v.4.0.2 (The R Project for Statistical Computing, www.r-project.org) with the 'rms' package utilized for logistic regression analysis and nomogram construction.A two-sided P-value less than 0.05 was considered statistically significant.

Patients' characteristics
As depicted in Table 1, a total of 601 eligible patients were included in this study.The entire cohort was randomly assigned to a training set (n = 421) and a validation set (n = 180).Among them, 97 patients experienced postoperative soiling, with 68 cases in the training set and 29 cases in the validation set.Statistical analysis revealed no significant differences between the training set and validation set (P > 0.05).The baseline characteristics of patients were given in Tables 1-2.

Identification of predictive factors
Given the multitude of variables involved, a two-step approach was employed to filter the clinical features.Firstly, a preliminary screening was performed using the LASSO regression to identify   3.Meanwhile, the nomogram also highlighted protective factors, including surgical history ( = 1), left colectomy, and other surgical procedures (Fig. 3).

Discrimination
For the sample, the C-index was 0.877 (95% CI: 0.828-0.926) in the training set and 0.878 (95% CI: 0.811-0.945) in the validation set, indicating that the model presented a good discriminative power.Additionally, the AUC values were determined to evaluate the discrimination of the nomogram.In the training set, the AUC for the nomogram to predict soiling was 0.896 (95% CI: 0.855 − 0.929).In the validation set, the AUC remained as high as 0.866 (95% CI: 0.767 − 0.920), further supporting the robust discriminative ability of the model (Fig. 4).

Clinical use
Moreover, the result of DCA indicated that the nomogram could yield significant net benefits for the patients experiencing soiling.[A] The optimal parameter [λ] selection in the LASSO model employed fivefold cross-validation using a minimum criteria approach.The optimal values of λ are represented by dotted vertical lines.Among these values, λ = 0.012, corresponding to a logarithm of λ equal to − 4.422, was selected as the optimal choice.[B] LASSO coefficient profiles of 12 clinical features.The plot was created using a logarithmic scale for the lambda values.A vertical line was added to indicate the lambda value selected through fivefold cross-validation.This optimal lambda value led to the identification of three features with nonzero coefficients.
Table 3 The prediction model with multivariate logistic regression.These benefits were observed within a risk threshold probability range of 1 to 73% in the training set and 3-69% in the validation set (Fig. 6).

Discussion
Despite significant advancements have been achieved in the management of HSCR in recent years, the occurrence of postoperative complications, particularly soiling, remains prevalent.Following surgery treatment, patients with HSCR often experience different degrees of soiling [6,17] .The occurrence of soiling can lead to various physical and psychological problems, ultimately exerting a negative impact on an individual's quality of life [30] .It has been suggested the etiology of postsurgical soiling in children can be attributed to three main factors: impaired sphincter function, dysfunction of the rectal reservoir, and diminished anal canal sensation [10,31] .And, impairment of any of these factors can compromise bowel control and result in the development of soiling [6] .Furthermore, additional factors such as the patient's age at the time of surgery and the type of surgical procedure performed also play a role in determining bowel function [6,17] .
Several studies have shown a correlation between postoperative soiling and the age of the patient undergoing surgical management.Previously, a study showed that some infants experienced a dramatic reduction in stool frequency after surgery for HSCR [32] .However, the specific mechanism behind this agerelated improvement remains unclear.Moreover, another study aimed to investigate the outcomes of patients with HCSR who underwent surgery prior to their first birthday was conducted, which demonstrated the differences of bowel functional decreased with age [6] .Nevertheless, the correlation between soiling and patients aged greater than 1 years operated for HSCR has never been thoroughly evaluated.With this in mind, we developed a nomogram for the first time to assess the risk of soiling in patients aged greater than 1 years operated for HSCR.
The Nomogram is a widely used prediction model in both oncologic and nononcologic diseases [33,34] .And, nomogram is established by integrating key factors to visualize the probability of clinical outcomes.A well-developed nomogram is a popular decision making tool that can be readily available to clinicians.
Currently, there is an absence of published nomograms that predict the occurrence of soiling in HSCR patients postoperatively.This is the first study to establish and validate a model for predicting the risk of soiling in patients aged greater than 1 years operated for HSCR.In this work, we determined that surgical history, length of removed bowel, and surgical procedures were the main factors associated with soling in patients with HSCR.A predictive model of soiling was developed based on the three factors, demonstrating favorable discrimination, calibration, and clinical utility.These findings indicating that the  model is valuable in identification and stratification of patients following operative management, which helps clinicians make an early intervention to reduce or avoid the occurrence of soiling.
Several studies have provided evidence to support the aforementioned three soiling-related risk factors.Prior studies have demonstrated that preserving the internal sphincter and preventing spur formation during surgery can decrease the risk of postoperative soiling [35,36] .And, proper sensory function relies on an undamaged anal canal, enabling distinction between solid, liquid, and gaseous rectal contents [37,38] .In the surgery, the anal canal may suffer damage if the distal end of the intraluminal dissection performed from above breaches into the anal canal [9] .Consequently, successive surgery and excessive surgical resections may impair the function of sphincter and the intact of anal canal, contributing to postoperative soiling.
Furthermore, the choice of surgical procedure also influences the development of postoperative soiling.For example, available researches indicated HSCR patients treated with the Duhamel procedure present with reduced postoperative soiling, as this surgical approach appears to minimize trauma to the anal canal [39] .The rectal sensation relies on perceiving stretching of the rectal walls and input from the specialized transitional epithelium demarcated by the dentate line.For HSCR pull-through procedures, the anastomosis should be performed 5-15 mm proximal to the dentate line [40] .Disrupting the dentate line during surgery may impair rectal awareness, leading to potential postoperative soiling.Heart-shaped anastomosis as a surgical procedure has been widely introduced to treat HSCR patients in our center [41] .The heart-shaped anastomosis surgical technique has several advantages compared to other methods like the Duhamel procedure.By removing only the posterior internal sphincter while preserving the anterior sphincter, it helps avoid complications like internal sphincter spasms and soiling issues after surgery.Additionally, since the rectocolic anastomosis is performed end-to-end, there is no risk of a blind rectal pouch or septum forming as can happen with the Duhamel procedure.The heart shape of the anastomosis also makes strictures and constipation less likely compared to other procedures [18,42] .Overall, the specific design of the heart-shaped anastomosis appears to minimize risks of common postsurgical problems like soing, strictures, and constipation.
In clinical practice, the developed model could estimate the probability of postoperative soiling in patients aged greater than 1 year operated for HSCR.Consequently, this model may assist clinicians in identifying patients who are at risk of suffering soiling subsequent to HSCR surgery, aiding in personalized patient care and management.As shown in Figure 3B, the patient experienced multiple surgeries (surgical history > 1), with the most recent procedure involving subtotal colectomy and Soave anastomosis.And, the estimated probability of soiling is 0.799.These results indicate that previous surgical history and length of removed bowel significantly impacts the subsequent occurrence of soiling, which is in lined with previous studies [43,44] .Accordingly, a comprehensive assessment involving a detailed history and clinical examination is imperative preceding additional operative interventions.Furthermore, in the case of highrisk patients, clinicians may choose more conservative surgical approaches and increased postoperative monitoring.In addition, utilizing the model results, clinicians can engage in comprehensive discussions of surgical risks with patients and families and manage patient expectations regarding surgical outcomes.These attributes may facilitate more satisfactory treatment results and cost-effective medical practices.

Limitations
There are some limitations in this work.First, due to the nature of retrospective study [45,46] , this study is inherently limited in its ability to establish causation.Moreover, some potentially factors influenced soiling, such as detailed dietary habits, postoperative care/compliance, and patient genetics are not available in our retrospective data, as we were constrained to the data available in the medical records.We believe that further prospective studies are needed to establish causation, validate the associations observed in our retrospective analysis.In addition, our model development and validation was done internally as the availability of data, which allowed us to fully optimize the model in a relatively controlled environment [47] but limited the generalizability of the model to other institutions.As is well-established, external validation offers a more rigorous assessment of model robustness, while noise or biases in external validation datasets may obscure the true model performance discovered through internal validation [48,49] .Finally, this study was conducted with patients from a single medical institution, it remains challenging to fully eliminate the selection bias and information bias associated with single-site samples.Hence, conducting multicenter and prospective cohort studies is imperative for a more thorough exploration [50,51] .
There are some limitations in this work.First, several potential factors, such as dietary habits, were not available in our data.In addition, it is important to acknowledge that the study might be limited to specific geographical areas.Therefore, the generalizability of the results to other regions necessitates further validation through the inclusion of data from external cohorts.

Conclusion
To the best of our knowledge, this is the first study to develop and verify a nomogram for predicting the risk of soiling in patients aged greater than 1 year operated for HSCR.Our model, which integrates surgical history, length of removed bowel, and surgical procedures was verified internally as a useful tool for risk assessment.The developed predictive model will be valuable in identification and stratification of patients following operative management.

Ethical approval
This study was approved by the Ethical Committee of Tongji Medical College of Huazhong University of Science and Technology (Ethical Committee S108) and conducted under the guidance of the Declaration of Helsinki.

A
nomogram was established by incorporating the aforementioned crucial clinical features.The nomogram revealed the relative contributions of each factor to the risk of soiling.According to the nomogram, Soave anastomosis was identified as the strongest predictor of soiling, followed by Duhamel anastomosis, surgical history ( > 1), total colectomy, Heart − Shaped anastomosis, Rehbein anastomosis, and subcolectomy.

Figure 2 .
Figure 2.[A] The optimal parameter [λ] selection in the LASSO model employed fivefold cross-validation using a minimum criteria approach.The optimal values of λ are represented by dotted vertical lines.Among these values, λ = 0.012, corresponding to a logarithm of λ equal to − 4.422, was selected as the optimal choice.[B] LASSO coefficient profiles of 12 clinical features.The plot was created using a logarithmic scale for the lambda values.A vertical line was added to indicate the lambda value selected through fivefold cross-validation.This optimal lambda value led to the identification of three features with nonzero coefficients.

Figure 3 .
Figure 3. [A] Nomogram with surgical history, length of removed bowel, and surgical procedures predicts the probability of soiling.[B] The dynamic nomogram reveals the surgical outcomes in a patient with HSCR.This patient experienced multiple surgeries [surgical history > 1], with the most recent procedure involving subtotal colectomy and Soave anastomosis.The estimated probability of soiling for this case is 0.799.

Figure 5 .
Figure 5. Calibration curves for the predicting probability of soiling in the training set [A] and [B] in the validation set, all P-value > 0.05 in the Hosmer-Lemeshow test suggested an agreement between the predicted probabilities and observed outcomes.

Figure 6 .
Figure 6.Decision curve analysis [DCA] for the soiling nomogram.The black line represents the assumption of no patient having soiling, while the gray line assumes that all patients experienced soiling.The blue line corresponds to the risk nomogram.The analysis was conducted on both the training set [A] and the validation set [B].

Table 1
Baseline characteristics between the soiling and nonsoiling groups.

Table 2
Baseline characteristics of participants in training and validation set.